From the Department of Neurology (R. Garza, A.J.G., B.L.B., Y.G.-M., A.L.G., D.L.K.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Pathology (B.B.G.), University of Texas Medical Branch, Galveston; Department of Family Medicine & Public Health (B.T.), University of Botswana, Gaborone; Departments of Medicine and Biostatistics (R. Gross), Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia; and Department of Medicine (S.L.L.), University of California, San Diego.
Neurol Neuroimmunol Neuroinflamm. 2020 Apr 10;7(3). doi: 10.1212/NXI.0000000000000710. Print 2020 May.
To determine whether regulatory variations in the heme oxygenase-1 (HO-1) promoter (GT) dinucleotide repeat length could identify unique population genetic risks for neurocognitive impairment (NCI) in persons living with HIV (PLWH), we genotyped 528 neurocognitively assessed PLWH of European American and African American descent and linked genotypes to cognitive status.
In this cross-sectional study of PLWH (the CNS HIV Antiretroviral Therapy Effect Research cohort), we determined HO-1 (GT) repeat lengths in 276 African Americans and 252 European Americans. Using validated criteria for HIV-associated NCI (HIV NCI), we found associations between allele length genotypes and HIV NCI and between genotypes and plasma markers of monocyte activation and inflammation. For comparison of HO-1 (GT) allele frequencies with another population of African ancestry, we determined HO-1 (GT) allele lengths in African PLWH from Botswana (n = 428).
PLWH with short HO-1 (GT) alleles had a lower risk for HIV NCI (OR = 0.63, 95% CI: 0.42-0.94). People of African ancestry had a lower prevalence of short alleles and higher prevalence of long alleles compared with European Americans, and in subgroup analyses, the protective effect of the short allele was observed in African Americans and not in European Americans.
Our study identified the short HO-1 (GT) allele as partially protective against developing HIV NCI. It further suggests that this clinical protective effect is particularly relevant in persons of African ancestry, where the lower prevalence of short HO-1 (GT) alleles may limit induction of HO-1 expression in response to inflammation and oxidative stress. Therapeutic strategies that enhance HO-1 expression may decrease HIV-associated neuroinflammation and limit HIV NCI.
为了确定血红素加氧酶-1（HO-1）启动子（GT）二核苷酸重复长度的调控变异是否可以识别出艾滋病毒感染者（PLWH）神经认知障碍（NCI）的独特人群遗传风险，我们对 528 名接受神经认知评估的欧裔和非裔 PLWH 进行了基因分型，并将基因型与认知状态相关联。
在这项针对 PLWH（中枢神经系统 HIV 抗逆转录病毒治疗效果研究队列）的横断面研究中，我们测定了 276 名非裔美国人 252 名欧裔美国人的 HO-1（GT）重复长度。我们使用与 HIV 相关的 NCI（HIV NCI）的验证标准，发现等位基因长度基因型与 HIV NCI 之间以及基因型与单核细胞激活和炎症的血浆标志物之间存在关联。为了比较 HO-1（GT）等位基因频率与另一个非洲裔人群，我们测定了来自博茨瓦纳的非洲裔 PLWH（n = 428）的 HO-1（GT）等位基因长度。
HO-1（GT）短等位基因的 PLWH 发生 HIV NCI 的风险较低（OR = 0.63，95%CI：0.42-0.94）。与欧裔美国人相比，非洲裔人具有较低的短等位基因频率和较高的长等位基因频率，在亚组分析中，短等位基因的保护作用仅在非裔美国人中观察到，而在欧裔美国人中则未观察到。
我们的研究确定了 HO-1（GT）短等位基因对 HIV NCI 的发展具有部分保护作用。它进一步表明，这种临床保护作用在非洲裔人群中尤其相关，其中 HO-1（GT）短等位基因的低流行率可能限制了对炎症和氧化应激的 HO-1 表达的诱导。增强 HO-1 表达的治疗策略可能会减少 HIV 相关的神经炎症并限制 HIV NCI。
